Abstract

The paradigm for hepatitis C virus (HCV) treatment relies on pegylated interferon and ribavirin (PR) as agents that enhance endogenous mechanisms for viral clearance and are dependent on host factors.1, 2 In May 2011, the US Food and Drug Administration (FDA) approved two new nonstructural 3 protease inhibitors, telaprevir (TVR) and boceprevir (BOC), as add-on therapy with the previous gold standard, PR, for HCV genotype 1–infected individuals. These protease inhibitors belong to a new class of direct-acting antiviral (DAA) agents that will usher in a new era of treatment for HCV infection.

For genotype 1–infected individuals, the addition of TVR or BOC to PR markedly improves sustained virological response (SVR) rates. However, the newly approved protease inhibitors are associated with increases in the frequency and severity of side effects, which will require additional management strategies to allow patients the maximum opportunity for achieving SVR. The treatment of genotype 1–infected, therapy-naive patients with TVR is based on a recent international phase 3 trial (ADVANCE) that randomized subjects into three groups.3 Group 1 received PR and a placebo for 48 weeks. Groups 2 and 3 received TVR for either 8 or 12 weeks in addition to PR with response-guided therapy (RGT). Patients in whom HCV RNA was undetectable at weeks 4 and 12 [i.e., an extended rapid virological response (eRVR)] stopped taking PR in week 24, whereas those patients in whom HCV RNA was detectable at week 4 but undetectable at week 12 continued to complete 48 weeks of PR. Significantly higher SVR rates were seen in the patients on the 12-week regimens with TVR (75%) versus the control patients receiving 48 weeks of PR (44%), and this 12-week duration of TVR has been licensed in the United States in combination with PR as an RGT paradigm (Fig. 1). More than half of the individuals who received this treatment in trials were able to truncate their therapy at 24 weeks, and this was confirmed in a supplementary trial called ILLUMINATE (Illustrating the Effects of Combination Therapy With Telaprevir) in which 12 weeks of TVR in addition to 24 or 48 weeks of PR was shown to be equivalent if patients achieved an eRVR.4 Subsequent approval by the FDA recommended that patients with cirrhosis be considered for a full 48-week course of PR in addition to TVR for 12 weeks, regardless of the initial response to treatment.

Figure 1. Treatment paradigm with futility rules for TVR and PR in treatment-naive individuals infected with HCV genotype 1. *The assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL. This figure is based on a TVR package insert (May 2011).

The approval of BOC was based on the Serine Protease Inhibitor Therapy 2 study, also called SPRINT 2, in which patients were randomized to 48 weeks of PR or to BOC plus PR in either an RGT arm or a fixed-duration arm. In all groups, a 4-week PR lead-in was used, and this was followed by the addition of BOC.5 In the RGT arm, patients in whom HCV RNA was undetectable during weeks 8 to 24 completed triple therapy at week 28, whereas patients in whom HCV RNA was detectable at week 8 but undetectable by week 24 discontinued BOC at week 28 and continued to complete another 20 weeks of PR for a total of 48 weeks of therapy. Patients in the fixed-duration arm received the lead-in treatment and then 44 weeks of BOC plus PR. The addition of BOC led to overall sustained response rates of 63% to 66% versus 38% in the PR-alone group.5 In this study, two cohorts were predefined as nonblack and black. The SVR rates in the nonblack cohort were 67% for the RGT arm and 68% for the 44-week (fixed-duration) BOC arm, and these rates were significantly higher than the rate for the PR control arm, for which an SVR rate of 40% was observed. In the black cohort, the SVR rate was 42% for the RGT arm, 53% for the 44-week BOC arm, and 23% for the PR control arm. The FDA subsequently approved an RGT paradigm for treatment with BOC. Specifically, if HCV RNA levels are undetected at weeks 8 and 24, individuals may be treated for 28 weeks. If HCV RNA is detected at week 8 and is undetected at week 24 (approximately half of treated patients), then patients should receive PR with BOC for 36 weeks and then a 12-week PR tail for a total of 48 weeks of therapy. Patients who have cirrhosis or respond poorly to PR (<1-log reduction after the PR lead-in treatment) should receive PR for 4 weeks and then 44 weeks of PR and BOC (Fig. 2). On the basis of these data, the American Association for the Study of Liver Diseases has revised its guidelines for the management of treatment-naive, HCV genotype 1–infected persons as follows6:

1.

The optimal therapy for chronic HCV genotype 1 infections is the use of BOC or TVR in combination with peginterferon-alfa and ribavirin (class 1, level A).

2.

BOC and TVR should not be used without peginterferon-alfa and weight-based ribavirin (class 1, level A).

3.

The recommended dose of BOC is 800 mg, and it should be administered with food three times a day (TID; every 7–9 hours) together with peginterferon-alfa and weight-based ribavirin for 24 to 44 weeks. This should be preceded by 4 weeks of a lead-in treatment with peginterferon-alfa and ribavirin alone (class 1, level A).

4.

Patients without cirrhosis who are treated with BOC and PR (preceded by 4 weeks of a lead-in treatment with PR) and in whom HCV RNA is undetectable at weeks 8 and 24 may be considered for a shortened treatment duration of 28 weeks in all (4 weeks of a lead-in treatment with PR followed by 24 weeks of triple therapy; class 2a, level B).

5.

Treatment with all three drugs (BOC, peginterferon-alfa, and ribavirin) should be stopped if the HCV RNA level is >100 IU/mL at treatment week 12 or HCV RNA is detectable at treatment week 24 (class 2a, level B).

6.

The recommended dose of TVR is 750 mg, and it should be administered with food (not low-fat food) TID (every 7–9 hours) together with peginterferon-alfa and weight-based ribavirin for 12 weeks followed by an additional 12 to 36 weeks of peginterferon-alfa and ribavirin (class 1, level A).

7.

Patients without cirrhosis who are treated with TVR and PR and in whom HCV RNA is undetectable at weeks 4 and 12 should be considered for a shortened therapy duration of 24 weeks (class 2a, level A).

8.

Patients with cirrhosis who are treated with either BOC or TVR in combination with PR should receive therapy for a duration of 48 weeks (class 2b, level B).

9.

Treatment with all three drugs (TVR, peginterferon-alfa, and ribavirin) should be stopped if the HCV RNA level is >1000 IU/mL at treatment week 4 or 12 and/or HCV RNA is detectable at treatment week 24 (class 2a, level B).

Figure 2. Treatment paradigm with futility rules for BOC and PR in treatment-naive individuals infected with HCV genotype 1. *The assay should have a lower limit of HCV RNA quantification ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10 to 15 IU/mL. TW, treatment week.

Triple antiviral therapy presents the provider and patient with new issues to address. Additional side effects and potential drug-drug interactions are part of the price that we pay for enhanced viral responses. With TVR, rashes, anemia, and gastrointestinal side effects are all more common than they are with PR alone. Rarely, Steven-Johnson syndrome or drug rash with eosinophilia and systemic symptoms has been reported, and this requires the immediate discontinuation of all drugs. However, the vast majority of patients are able to continue treatment despite rashes, and with careful management, a high SVR rate can still be achieved. With BOC, the primary additional side effect is anemia. Finally, drug-drug interactions will be important. There is a list of contraindicated medicines for both of these drugs that must be addressed before the initiation of therapy (Table 1). These will be discussed in more detail in the second issue of Clinical Liver Disease.

Sildenafil or tadalafil for treatment of pulmonary arterial hypertension

Sildenafil or tadalafil for treatment of pulmonary arterial hypertension

Sedatives/hypnotics

Triazolam and orally administered midazolam

Orally administered midazolam and triazolam

In summary, the era of DAA agents has arrived. Approximately 70% of treatment-naive, genotype 1–infected individuals now may be treated successfully with PR plus DAA agents with RGT. High SVR rates have also been seen across difficult-to-treat groups, including patients with high viral levels, patients with advanced fibrosis, and black patients. Moreover, treatment may now be truncated at 6 months in approximately half of individuals. Finally, as we enter the era of DAA-based therapy for HCV, strict adherence to treatment futility rules should be maintained to prevent the emergence of resistance-associated variants that might hamper future therapy.